The attention of investigators interested in pain has in recent years been increasingly directed towards understanding mechanisms that form the basis for hyperalgesia and persistent pain states. The greatest effort has been on elucidating the now well-documented plasticity of elements in nociceptive transmission pathways, with demonstrated sensitization of both the primary afferent nociceptors and dorsal horn processing circuits. By contrast, the possibility that changes in brainstem descending modulatory systems might contribute to persistent pain states has received comparatively little attention. Nevertheless, there is now mounting evidence pointing to an important role for these modulatory systems in hyperalgesia and persistent pain. The best characterized modulatory system, with important links in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), was long viewed as an "analgesia system," activated by acute stress or pain or by opioid analgesic drugs to inhibit spinal nociceptive processing. It is now thought to be more complex, enhancing or inhibiting nociception under different conditions. The overall goal of the work proposed here is to identify neural mechanisms for bi-directional control by this brainstem pain modulating system, focusing on two populations of putative nociceptive modulatory neurons that have been identified in the RVM: "off-cells," proposed to inhibit nociceptive processing, and "on-cells," proposed to facilitate nociception. Our approach will involve a combination of behavioral pharmacology with single cell recording techniques and microiontophoresis to understand how these physiologically distinct classes of RVM neurons might be recruited, and to further define the contribution of each class to pain modulation. The role of brainstem pain modulating systems in opioid analgesia is well documented, but neural mechanisms through which these systems contribute to pain facilitation are so far almost completely unknown. The proposed work should advance our understanding of central processes involved in bi-directional pain modulation, and should ultimately lead to improved clinical treatment of pain.